The first suggestion of FGF21 as a mitokine dates from 2013 when Kim et al. showed that skeletal muscle–specific deletion of Atg7 (autophagy-related 7) induced autophagy deficiency in mice led to the protection from obesity and insulin resistance by inducing Fgf21 [105]. This evidence concerns the gene FGF21 and obesity due to melanocortin 4 receptor deficiency.